Neuropeptides: keeping the balance between pathogen immunity and immune tolerance

Abstract

Various neuropeptides have emerged recently as potent immunomodulatory factors with potential for their therapeutic use in immune disorders. Here we highlight the most recent data relevant in the field and we offer our opinion on how neuropeptide therapy might impact clinical immune diseases, and the challenges in this field that must be overcome before achieving medical progress. We also review recent reports describing the antimicrobial effects showed by some neuropeptides and the therapeutic, physiological, and evolutionary consequences of this new finding. Finally, we discuss how a physiologically functional neuropeptide system contributes to general health and how neuropeptides educate our immune system to be tolerant.

Figure 1. Regulation of the inflammatory and autoimmune responses by neuropeptides

Grey boxes depict the mechanisms involved on the inhibition of inflammation and autoimmunity by neuropeptides. Black arrow, stimulation. Back-crossed line, inhibition. ▲, increase; ▼, decrease. Treg, regulatory T cells; Tr-1, type 1 Treg; DC, dendritic cells; MΦ, macrophages; NO, nitric oxide; PGE2, prostaglandin E2; PPARγ, peroxisome proliferator-activated receptor-γ; HMGB1, high-mobility group box-1; IL, interleukin; TNF, tumor necrosis factor; IL-1Ra, IL-1 receptor antagonist.

Figure 2. Antimicrobial activity of neuropeptides

A. Neuropeptide sequences indicating hydrophobic (green) and positive-charged (blue) residues. Shadow areas indicate potential interacting motifs of neuropeptides with microbial membranes. Three-dimensional models for charge distribution in the peptides are shown (blue region: positive charge; red region, negative charge; white region, neutral charge). B. Neuropeptides inhibit cell cycle and budding-to-hyphal-form transition on yeast. C. After their binding to bacteria surface, neuropeptides can form membrane pores or destabilize membrane compromising membrane integrity/permeability or can inhibit the formation of septum which is essential for bacterial division. D. Cationic neuropeptides are endocytosed by parasites and alter cellular traffic and parasite metabolism, disrupt lysosomes and induce autophagy-like cell death. AM, adrenomedullin; VIP: vasoactive intestinal peptide; GHR, ghrelin; MSH, melanocyte-stimulating hormone; UCN, urocortin.